4,9alpha-dihalo-11-oxygenated derivatives of progesterone



- 2,897,199 Patented July 28, 1958 4,9a- DlHAL0-11-OXYGENATED DERIVATIVES 0F PROGESTERONE Howard J. Ringold and Enrique Batres, Mexico City, Mexico, assignors to Syntex S.A., Mexico City, Mexico,

a corporation of Mexico Application September 10, 1958 Serial No. 760,088

Claims priority, application Mexico September 11, 1957 17 Claims. (Cl. 260-23955) .No Drawing.

The present invention relates to novel cyclopentanophenanthrene compounds.

More particularly the present invention relates to 4,9- dihalo-ll-keto or hydroxyv derivatives of progesterone. The novel compounds of the present invention just described are progestational hormones. In addition they exhibit a strong anti-leukemic eflect, i.e. causing lysis of leukemic cells in vitro. Further since they may be conventional means be provided with a 21-hydroxy group and a l7a-hydroxy group they are valuable intermediates for the production of the corresponding 4,9a-dihalo derivatives of cortisone and hydrocortisone which are valuable anti-inflammatory drugs.

-In accordance with the present invention the aforementioned novel compounds were prepared from Ila-hydroxy progesterone by forming therefrom 45,5;3-oxidopregnan-l1u-ol-3,20-dione, opening the epoxide with a hydrogen halide to form the corresponding 4-halo-1lahydroxy-progesteroneand thereafter introducing the 90:- halo group by the same type of reaction disclosed by Fried and Sabo J.A.C.S. 79, 1130 (1957).

The novel compounds of the present invention are illustrated by the following formula:

In the above formula X represents=0 or R represents fluoro, bromo or chloro, and R represents chloro or bromo.

The novel compounds above set forth are prepared by a process illustrated by the following equation.

chloride 7 sodium acetate acetic acid hypobromous --b 0: acid a t l I oxidation l ggegi e $113 $15k CO C0 t; t l

2 I I V I yidation 1 CH:

R4 l I In the above equation R and R represent the same groups as heretofore. R represents lower alkyl or aryl, R represents chlorine or fluorine.

In practicing theprocess above outlined lla-hydroxy progesterone is reacted with hydrogen peroxide in alkae line medium to prepare 45,5/3-oxido-pregnan-l1a-ol-3g20 dione, reaction of this last compound with hydrochloric acid or hydrobromic acid gave the 4-chloro-lla-hydroxyprogesterone or the 4-bromo-1loz-hydroxy-progesterone respectively. These compounds upon reaction with a lower alkyl or aryl sulfonyl chloride gave the respective alkyl sulfom'c or aryl sulionic ester which was treated with sodium acetate in acetic acid solution to give the respective 4-halo-A -preguadien-3,20-dione compound. By addition of hypobromous acid there was then produced the respective 4-halo (chloro or bromo)-9u-bromollfl hydroxy-progesterone. These compounds upon refluxing with potassium acetategave the respective 95,115;

oxido derivatives which when opened with hydrochloric or hydrofluoric acid gave the 4,9a-diha1o-11fi-hydroxyprogesterones indicated in the equation. Conventional oxidation then gave the corresponding ll-keto derivatives.

The following specific examples serve to illustrate but are not intended to limit the present invention.

Example I and ice and extracted with methylene dichloride;.-the

extract was washed with water to neutral, dried and completely evaporated, thus leaving a crystalline mass which was chromatographed with 300 g. of alkaline alumina; elution with benzene-ether afforded 4,8,5B-oxido-pregnanlla-ol-3,20-dione which was recrystallized from methanol.

8 g. of. the above epoxide was dissolved in 120 cc. of acetone and treated at room temperature with 8 cc. of concentrated hydrochloric acid; after 45 minutes it was poured into water, cooled and the precipitate was filtered and dried on the steam bath. There was thus obtained 4-chloro-lla-hydroxyprogesterone which upon crystallization from acetone yielded the pure substance.

A solution of 5 g. of the above 4-chloro-l1a-hydroxyprogesterone in 20 cc. of chloroform and 25 cc. of anhydrous pyridine was cooled to C. and mixed 7 g. of tosyl chloride, with stirring and maintaining the temperature at 0 C. The stirring was continued for 4 hours at 0 C. and then at room temperature for 15 hours. was added and the mixture was diluted with water and extracted with chloroform. The extract was washed with water, dilute hydrochloric acid, sodium carbonate solution and finally with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue was dissolved in absolute ethanol and upon concentration and cooling there was obtained the lloz-tOSYlatC of 4-chloro-progesterone.

6 g. of the lla-tosylate of 4-chloro progesterone was slowly added to a stirred solution of 8 g. of anhydrous sodium acetate in 70 cc. of glacial acetic acid and the mixture was heated to a temperature around 110 C.

After refluxing for half an hour the mixture was cooled in an ice bath and slowly diluted, with stirring, with 100 cc. of water. The precipitate formed was collected and washed with dilute hydrochloric acid and water. There Was thus obtained 4-chloro-A -pregnadien-3,20-dione. The analytical sample was obtained by recrystallization from ethyl acetate.

A mixture'of' 5 g. of 4-ChlOI'0-A a 1)-pregnadien3,20- dione, 5 cc. of dioxane and 7 cc. of 0.5 normal perchloric acid was treated with 2.3 g. of N-bromoacetamide in the course of 1 hour, while the mixture was stirred in the dark. The stir-ring was continued for one hour further and then 10% aqueous sodium sulfite solution was added until the reaction with potassium iodide-starch paper no longer gave a blue color. Ice was added followed by 50 cc. cit-chloroform and the organic layer was separated and washed with water, taking care that the temperature of the solution did not rise over C. by the addition ofpieces of ice. The extract was evaporated under reduced pressure in a bath kept below C. The remaining'syrupy residue was triturated with 20 cc. of acetone and cooled in the refrigerator for several hours. The precipitate was'filtered and the filtrate was concentrated to give a second crop upon cooling. There was thus obtained 4-chloro-9m-bromo-l lfl-hydroxyprogesterone.

* A solution of 4 g.- of anhydrous potassium acetate in 40- cc. of absolute ethanol was' heated nearly to boiling and then there was-added asolution of 5 g. of 4-chloro- Ice 9a -bromollB-hydroxyprogesterone, obtained. as described above, in 20 cc. of dioxane. The mixture was refluxed for 40 minutes, cooled in an ice bath, treated with 90 cc. of ice water and vigorously stirred, thus giving 4chloro-9fl,1lfi-oxido-M-pregnen,20-dione. Con centration of the mother liquors afiorded an additional amount of the same compound. The analytical sample was obtained by recrystallization from acetone.

A solution of 4 g. of 4-chloro-9 8,1lp-oxido-A epregnon-3,20-dione in 40 cc. of redistilled chloroform was treated with cc. of a 0.45 normal cold chloroform solution of dry hydrogen chloride, which was added in the course of minutes whilerthe mixture was kept around 0 C. It was kept at 0 C. for one hour, water was added, the chloroform layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The crystalline residue was purified by recrystallization from acetone, thus producing 4,9a-dichloro-1lfl-hydroxyprogesterone.

Example 11 A solution of 5 g. of 4-chloro-9l9-,llfi-oxido-M-pregnen 3,20-dione, prepared in accordance with the method of the previous example, in 110 cc. of redistilled chloroform was placed in a polyethylene bottle fitted with a mechanical stirrer and cooled to 0 C. There was then introits weight by 0.6 g., which took approximately 20 minutes.

The mixture was kept for 2 hours more at 0- 'C.. and

then there was cautiously added a suspension of sodium bicarbonate in water, with stirring, until the mixture showed a weakly alkaline reaction. The mixture-was transferred to a separatory tunnel and the chloroform layer'was separated, washed with water, 5% sodium carbonate solution and water, dried over anhydroussodium sulfate, filtered and evaporated to dryness under rednced pressure. The residue crystallized from ethyl acetate, thus yielding 4-chloro-9a-fluoro-llfl-hydroxyprogesterone.

Example 111 When in the method of Example I 4-chloro-9/3,llfioxido-A -pregnen-3,20-dione was substituted by 4-bromo- 913,11fi-oxido-M-pregnen-Z:,20-dione, there was obtained 4- 'bromo-9a-fluo'ro-1 1/8-hydroxyprogesterone.

Example V A solution of 1 g. of 4-chloro-9wfiuoro-llp-hydroxyprogesterone, described in Example II, in 30 cc. of acetic acid was treated with a solution of 400 mguof chromium trioxide in 6 cc. of acetic acid and the mixture was stirred at room temperature for 2 hours. After pouring into ice water the precipitate was filtered, washed with water, dried under vacuum and recrystallized from acetone, thus yielding 4-chloro-9a-fluoro-1l-keto-progesterone.

Example VI By the method of the previous example, there were oxidized the other 4,9a-dihalo-1l-hydroxy com-pounds described in Examples I to IV, to form the corresponding ll-keto compounds. There were thus obtained: 4-chloro- 9a bromo ll-ketoprogesterone, 4,9a-dibromo-11-ketoprogesterone, 4,90; dichloro-ll-ketoprogesterone, 4-bro- 5 mO-9a-ch1oro-1l-ketoprogesterone and 4-bromo-9 oc-flIlOI'O- 1 l-ketoprogesterone.

Example VII In the preparation of 4-chlor0-A -pregnadien-3,20-

5 dione described in Example I, there was substituted the tosyl chloride by mesyl chloride, thus producing as an intermediate the llu-mesylate of 4-chloro-11u-hydroxyprogesterone.

We claim: 1 1. A compound of the following formula:

R2 wherein X is selected from the group consisting of =0 and R1 is selected from the group consisting of fluoro, bromo and ehloro and R is selected from the group consisting of chloro and Jerome.

. 4-chloro-9 u-bromo-A -pregnen-1 l B-ol-3 ,ZO-dione.

. 4,9a-dibromo-A -pregnen-1 113-01-3 ,20-dione.

4-bromo-9ez-chloro-A -pregnen1 1B-ol-3,20-dione. 4-bromo-9a-fluoro-M-pregnen-1 l {3-01-3 ,20-dione.

. 4-ch1oro-9u-bromo-A -pregnen-3,l1,20-trione.

. 4,9a-dichloro-A -pregnen-3,l1,20-trione.

1 1. 4,9u-dibromo-A -pregnen-3,1 1,20-trione.

12. 4-bromo-9u-chloro-A -pregnen-3,1 1,20-trione.

13. 4-bromo-9u-fluoro-A -pregnen-3,11,20-trione.

14. 4-ch1oro-A -pregnadien-3,20-dione.

15. 4-bromo-A -pregnadien-3,20-dione.

l6. 4-chlor0-9 3,11 fl-oxido-A -pregnen-3,20-dione.

17. 4-bromo-9fi,lLB-oxido-M-pregnen,ZO-dione.

Krsek Jan. 24, 1956 Fried Dec. 10, 1957 

16. 4-CHLORO-9B,11-B-OXIDO-$4-PREGNEN-3,20-DIONE. 